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Biomedical subjects

A A Hislop

Publications and source records attributed to A A Hislop.

At least 19 recordsLinked to original sources
PubMed2005

Role of atrial septostomy in the treatment of children with pulmonary arterial hypertension.

OBJECTIVES: To assess in retrospect the safety and effectiveness of atrial septostomy in children with severe pulmonary arterial hypertension without an intracardiac communication. METHODS: 20 patients were reviewed retrospectively, 19 with idiopathic pulmonary arterial hypertension. The mean age at septostomy was 8.4 years (range 3 months to 17 years). Graded balloon septostomy alone was carried out in eight patients, a blade septostomy was done in two, a blade septostomy plus graded balloon septostomy was done in three, and a fenestrated device was inserted in seven. RESULTS: There were no fatalities. Four children suffered complications during the procedure. None had further syncope and all improved symptomatically with a significant (p < 0.01) decrease in World Health Organization functional class (mean shift -0.6) and a significant improvement in the semiquantitative echocardiographic assessment of right ventricular function (p < 0.03). The mean oxygen saturation decreased by 7.8 percentage points. The atrial communication closed in two children, necessitating a repeat procedure. After a mean follow up of 2.1 years (range one month to 6.7 years), 18 of 20 children are still alive. CONCLUSION: Atrial septostomy improved symptoms and quality of life in a group of children deteriorating with severe pulmonary arterial hypertension. This procedure is to be recommended for severely symptomatic children, before they become critically ill. Fenestrated devices may help ensure indefinite patency of the atrial communication.

Adolescent↗
PubMed2005

Response to bosentan in children with pulmonary hypertension.

OBJECTIVE: To describe an early experience of treating 40 children with the dual endothelin receptor antagonist bosentan, which is known to be safe and effective in adults with pulmonary hypertension (PH). DESIGN: In this retrospective, observational study the UK Service for Pulmonary Hypertension for children treated 40 children with bosentan, 20 with idiopathic pulmonary arterial hypertension (IPAH) (mean age 8.03 years, range 1.2-17) and 20 with PH associated with other conditions (congenital heart disease, parenchymal lung or connective tissue disease, or HIV). Their mean age was 8.3 years (range 0.6-16 years). PATIENTS: 39 patients were in World Health Organization (WHO) class III and IV, and all had shown recent deterioration. In IPAH the mean pulmonary vascular resistance (PVR) was 21.7 units.m2 (range 5.6-42.8). In secondary PH the mean PVR was 18 units.m2 (range 4.9-49). No child had a positive response to vasodilator testing with nitric oxide. INTERVENTIONS: Bosentan was given as first line treatment to 25. Nine were given intravenous epoprostenol. Children were treated for a mean of 12.7 months (range 2-24 months). MAIN OUTCOME MEASURES: Response to treatment was judged by WHO functional class, six minute walk test, weight, ECG and echocardiographic findings, and need to add additional treatment. RESULTS: Bosentan was well tolerated. In the IPAH group 19 (95%) stabilised with bosentan treatment but 12 (60%) patients needed combined treatment with epoprostenol. In secondary PH, WHO class, six minute walk test, and weight gain improved significantly. CONCLUSION: Bosentan helped stabilise children with IPAH but intravenous epoprostenol was also needed by 60%. Children with secondary PH improved.

Adolescent↗
PubMed2002

Birth upregulates nitric oxide synthase activity in the porcine lung.

Developmental changes in the lung occur at birth, allowing for the transition from placental to air breathing. Here we have measured nitric oxide synthase (NOS) activity in the porcine lung pre and post partum. NOS activity, which was predominantly calcium dependent, was low in full term fetal tissue compared to that present in lungs from the newborn (5 minutes post partum), 1, 3, 6 and 14 day old animals. No increase in activity was seen when fetal pigs were allowed to breathe for 5 minutes. Specific activity remained low in fetal tissue following partial purification. By contrast, levels of NOS III protein in tissue extracts and in pulmonary arterial endothelial cells, demonstrated by immunohistochemistry, were similar in tissue from the fetal and newborn animals. Thus NOS activity is significantly lower in fetal when compared to postnatal lung tissue despite comparable amounts of NOS III protein being expressed, and birth is followed by an abrupt increase in enzyme activity in animals born at term which correlates with an increase in protein expression.

Aging↗
PubMed2000

Birth associated changes in pulmonary arterial connective tissue gene expression in the normal and hypertensive lung.

OBJECTIVES: To determine the temporal and spatial expression of the connective tissue precursors, procollagen and tropoelastin mRNA in normal and pulmonary hypertensive porcine pulmonary arteries from birth onwards. METHODS: Using in situ hybridisation, connective tissue gene expression for procollagen alpha1(I) and alpha1(III) and tropoelastin was studied in intrapulmonary arteries from normal piglets, 5 min-16 weeks, and from piglets made pulmonary hypertensive by exposure to hypobaric hypoxia for 3 days, from birth, 3 or 14 days of age. In addition, Type III pN-procollagen, tropoelastin and collagen I and III were studied by immunohistochemistry. Quantitative or semi-quantitative techniques were applied to both in situ and immunohistochemical studies. RESULTS: Procollagen alpha1(I) and alpha1(III) mRNA expression increased rapidly in the media and adventitia between birth and 3 days of age (P<0.05). The increase was transient and the number of cells expressing procollagen mRNA decreased to the low newborn number after 6 days of age. Type III pN-procollagen immunostaining was greatest in newborn elastic and muscular arteries and then decreased. Collagen I and III increased mainly after 6 days of age. In animals exposed to chronic hypobaric hypoxia from birth, the increase in procollagens I and III mRNA was prevented. Exposure to hypoxia from 3 or 14 days led to little change in either gene expression or in procollagen and mature collagen from the normal. Tropoelastin gene expression was high at birth in the endothelium and media for the first 6 days, and then decreased. Normally, tropoelastin decreased in the media and increased in the adventitia after 16 days of age. Hypoxia had no effect on the mRNA but led to increased tropoelastin. CONCLUSION: We demonstrated marked, rapid changes in temporal and cell specific connective tissue gene expression in normal pulmonary arteries immediately after birth as the vasculature remodels. Each gene appeared to have its own timetable of expression and responded differently to hypoxia-induced hypertension.

Animals↗
PubMed2000

Growth of the vascular tree.

Major changes occur in the pulmonary circulation at birth. Failure of normal adaptation leads to pulmonary hypertension of the newborn. The basis for this may be abnormal growth of the lung in utero or a failure of the mechanisms which lead to vasodilatation in the newborn period. This article describes normal development of the pulmonary arteries and veins, their branching pattern and structure and discusses the factors which may control this growth. Endothelial function and dysfunction are crucial in adaptation, and new experimental studies are aiding our understanding of the control and action of factors produced by the endothelium, e.g. nitric oxide, prostacyclin and endothelin. The study of infants with pulmonary hypertension, together with the experimental studies, will aid in producing effective methods of controlling increased pulmonary artery pressure in the newborn period.

Adaptation, Physiological↗
PubMed2000

Prenatal origins of human intrapulmonary arteries: formation and smooth muscle maturation.

Recent studies on the morphogenesis of the pulmonary arteries have focused on nonhuman species such as the chick and the mouse. Using immunohistochemical techniques, we have studied 16 lungs from human embryos and fetuses from 28 d of gestation to newborn, using serial sections stained with a panel of antibodies specific for endothelium, smooth muscle, and extracellular matrix proteins. Cell replication was also assessed. Serial reconstruction showed a continuity of circulation between the heart and the capillary plexus from at least 38 d of gestation. The intrapulmonary arteries appeared to be derived from a continuous expansion of the primary capillary plexus that is from within the mesenchyme, by vasculogenesis. The arteries formed by continuous coalescence of endothelial tubes alongside the newly formed airway. Findings were consistent with the pulmonary arterial smooth muscle cells being derived from three sites in a temporally distinct sequence: the earliest from the bronchial smooth muscle, later from the mesenchyme surrounding the arteries, and last from the endothelial cells. Despite their different origins, all smooth muscle cells followed the same sequence of expression of smooth muscle-specific cytoskeletal proteins with increasing age. The order of appearance of these maturing proteins was from the subendothelial cells outward across the vessel wall and from hilum to periphery. The airways would seem to act as a template for pulmonary artery development. This study provides a framework for studying the signaling mechanisms controlling the various aspects of lung development.

Actins↗
PubMed1999

Role of NO in recovery from neonatal hypoxic pulmonary hypertension.

BACKGROUND: The management of sick newborn infants who have sustained a hypoxic insult is a common clinical problem but relatively little is known about the recovery process. The aim of this study was to investigate this process in newborn piglets. METHODS: Thirty five newborn piglets were exposed to chronic hypobaric hypoxia for three days, either from birth, three or 14 days of age, and were allowed to recover for one, three, or six days. Control animals of relevant age were also studied. The heart weight ratio and pulmonary arterial muscularity were measured. Endothelial dependent and independent relaxation of the isolated intrapulmonary conduit arteries was determined in classical organ chamber studies, together with measurement of basal and stimulated cGMP accumulation. RESULTS: After six days of recovery the hypoxia induced right ventricular hypertrophy and pulmonary arterial medial hypertrophy had decreased in all animals but values were still abnormal in the two younger age groups. Relaxation was still impaired during the first three days of recovery in all groups, had normalised by six days in the two youngest groups, but relaxation (both endothelium dependent and independent) remained impaired in older animals. In these older animals basal nitric oxide (NO) production and basal and stimulated cGMP accumulation was normal. CONCLUSIONS: The recovery of the smooth muscle cells lags behind that of the endothelial cells. A normal stimulated increase in cGMP with reduced relaxation suggests an altered threshold for cGMP effected relaxation. These findings help to explain why some hypoxic infants require protracted NO therapy.

Acetylcholine↗
PubMed1999

Newborn intrapulmonary veins are more reactive than arteries in normal and hypertensive piglets.

The reactivity of pulmonary veins during adaptation from pre- to postnatal life is not well characterized. With an in vitro organ bath technique, the responses to the contractile and relaxant agonists U-46619 (10(-10) to 3 x 10(-6) M) and acetylcholine (10(-9) to 10(-4) M) were compared in adjacent conduit pulmonary vein and artery rings from 66 piglets aged 1 wk preterm to 14 days of postnatal life and from adult tissue. Five additional piglets were made hypertensive by exposure to chronic hypoxia for 3 days after birth. Both arteries and veins showed smaller contractile and relaxant responses before birth than after. By 5 min after birth, the contraction by arteries and relaxation by veins had increased (P < 0.05). By 3 days of age, arterial relaxation increased, but in all animals, venous relaxation exceeded that in arteries (P < 0.05). Veins contracted more than arteries in animals aged 3-14 days. Neonatal hypoxia diminished the responses to both agonists in the veins (P < 0.05), whereas the response in the arteries remained similar to that in the normal newborn. We speculate that veins may be more important in postnatal adaptation than previously suggested.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1999

Changes in ANP responsiveness of normal and hypertensive porcine intrapulmonary arteries during maturation.

Pulmonary vascular resistance falls rapidly after birth, but endothelium-dependent relaxation is relatively poor during the perinatal period. Atrial natriuretic peptide (ANP) is a potent vasodilator; however, its role in the process of perinatal adaptation is uncertain. Porcine intrapulmonary conduit arteries (IPA) from fetal, newborn (< 5 min), 3-, 6-, and 17-d-old, and adult pigs, and from piglets made hypoxic from 0 to 3, 3 to 6, or 14 to 17 d, were isolated and mounted for isometric force recording. Rings were precontracted with prostaglandin-F2 alpha (PGF2 alpha, 10 microM) or KCl (40 mM). ANP was added cumulatively (10 pM to 100 nM). C-type natriuretic peptide (CNP) was added as a single concentration of 100 nM. Accumulation of cGMP under basal conditions and stimulated by ANP or CNP was measured by radioimmunoassay system. Frozen sections of lung tissue were incubated with 125I-labeled alpha-ANP, and binding site density was assessed on IPA with an image analysis system. ANP relaxed IPA in pigs at all ages, but the effect was significantly greater at 6 and 17 d of age. Hypoxia in animals from 14 to 17 d old impaired ANP-induced relaxation. CNP relaxed IPA poorly: < 12% at all ages. ANP increased cGMP accumulation in both normal and hypoxic animals. CNP did not increase cGMP generation in IPA from normal animals but did so in IPA from 3-d-old hypoxic animals. ANP-specific binding sites were demonstrated on the pulmonary artery smooth muscle cells, with greater binding in the young animals. The increased relaxant responses to ANP during adaptation may be important in maintaining low pulmonary vascular resistance. In contrast, CNP was largely ineffective in relaxing pulmonary arteries.

Age Factors↗
PubMed1998

Muscarinic receptor subtypes in the porcine lung during postnatal development.

The responsiveness of the pulmonary circulation to acetylcholine changes in the newborn piglet. Therefore muscarinic receptors have been studied in the developing porcine lung from birth to adulthood using ligand binding, Northern blotting and in situ hybridisation. Maximal binding capacity of [N-methyl-3H] scopolamine and the affinity of the receptor in lung membranes increased between birth and 16 days (p < 0.05). Subtype affinity changed with age, but always M3, > M1 > M2. Northern blots of porcine muscarinic receptor subtypes showed m1, m2 and m3 mRNA present in lung membranes. m2 mRNA was present at all ages and decreased with age. m1 mRNA was absent at birth and m3 mRNA was absent at 3 days. Autoradiographic localisation showed ligand binding to the parenchyma and airway smooth muscle and nerves, there was no binding to intrapulmonary vessels. In situ hybridisation localised mRNA of all three subtypes to the smooth muscle cells of both vessels and airways. Changes in the receptor subtypes may explain the pharmacological changes during postnatal adaptation.

Animals↗
PubMed1998

Lung growth after transplantation of an adult lobe of lung into a juvenile rat.

OBJECTIVE: Shortage of donor organs for children has led to the use of living related adult lung lobar transplants. It is not known how these lobes or the recipient remaining lung grow after such transplants. The purpose of the present study was to assess lung growth in rat lungs up to 6 months after adult lobe transplantation into a juvenile recipient. METHODS: Right cardiac lung lobes from adult male Lewis rats were transplanted into the left hemithorax of juvenile (6-week-old) male Lewis rats after left pneumonectomy. Animals with appropriate controls were put to death 14 days and 6 months after transplantation. The lungs were fixed inflated and studied by means of quantitative morphometric techniques. RESULTS: By 6 months after transplantation both the recipient right lung and the transplanted cardiac lobe were significantly larger than normal (p = 0.005; p = 0.001). In the recipient right lung this increase was due to an increase in the number of alveoli (p = 0.004) and in the transplanted cardiac lobe to an increase in size of the alveoli (p = 0.008). CONCLUSIONS: An adult lobe transplanted into a young recipient is still viable and has normal architecture after 6 months, and growth of the recipients' own lung continues. The outlook for comparable transplants in children is promising, although the human condition can be complicated by rejection, infection, and treatment strategies.

Age Factors↗
PubMed1998

Developmental changes in binding sites and reactivity for CGRP and VIP in porcine pulmonary arteries.

During postnatal adaptation pulmonary arteries dilate. CGRP and VIP are pulmonary vasodilators. In this report, porcine lungs from newborn to adult were studied. Radiolabeled ligand binding and autoradiography showed CGRP binding sites on the endothelium of pulmonary arteries and veins, which increased postnatally, and VIP binding sites on smooth muscle, which decreased. Isolated conduit arteries relaxed normally (initially endothelium dependent) in response to CGRP from birth. VIP first caused relaxation at 10 days and was endothelium dependent. Age-related changes in receptor binding density were not always reflected in an appropriate alteration in pharmacological response.

Adaptation, Physiological↗
PubMed1998

Structural considerations. Early intervention in childhood asthma.

Any therapeutic treatment applied to a developing and/or growing organism is complicated by the fact that the treatment window may hit a critical stage of a developing organ. This means that unlike administration in adults, dosage and timing of drug applications are important issues because of their possible damaging effects. In view of the timing of lung developmental phases, it appears that perinatal interferences by diseases, environmental influences or drugs will affect specifically alveolar development and microvascular maturation. Numerous publications report, that the developing lung can be disturbed by a variety of factors, such as temperature, oxygen tension, cigarette smoke, malnutrition, drugs and hormones, in particular glucocorticoids. In well-documented animal experiments perinatal glucocorticoid treatment, even in very low doses, inhibited alveolization. This effect has been analysed in more detail and a hypothesis for its mechanism has been presented. The above effects on lung development may be extremely difficult to assess in human infants by noninvasive techniques. The message, however, remains that potent drugs should be used with great reservation.

Adult↗
PubMed1997

Endothelial nitric oxide synthase in hypoxic newborn porcine pulmonary vessels.

AIMS: To determine if the failure of neonatal pulmonary arteries to dilate is due to a lack of nitric oxide synthase (NOS). METHODS: A monoclonal antibody to endothelial NOS was used to demonstrate the distribution and density of NOS in the developing porcine lung after a period in hypobaric hypoxia. Newborn piglets were made hypertensive by exposure to hypobaric hypoxia (50.8 kPa) from < 5 minutes of age to 2.5 days of age, 3-6 days of age or 14-17 days of age. A semiquantitative scoring system was used to assess the distribution of endothelial NOS by light microscopy. RESULTS: NOS was present in the arteries in all hypoxic animals. However, hypoxia from birth caused a reduction in NOS compared with those lungs normal at birth and those normal at 3 days. Hypoxia from 3-6 days led to a high density of NOS compared with normal lungs at 6 days. Hypoxia from 14-17 days had little effect on the amount of NOS. On recovery in room air after exposure to hypoxia from birth there was a transient increase in endothelial NOS after three days of recovery, mirroring that seen at three days in normal animals. CONCLUSIONS: Suppression of NOS production in the first few days of life may contribute to pulmonary hypertension in neonates.

Analysis of Variance↗
PubMed1997

Influence of hypoxia on endothelin-1 binding sites in neonatal porcine pulmonary vasculature.

Exposure to chronic hypobaric hypoxia in the newborn piglet causes pulmonary hypertension and structural abnormalities in the intrapulmonary arteries that resemble those seen in babies with pulmonary hypertension of the newborn. To investigate whether the density and subtype of endothelin (ET) receptors in intrapulmonary arteries were altered by exposure to chronic hypobaric hypoxia (50.8 kPa) and changed on recovery, (125)I-labeled ET-1 binding was studied using an in vitro autoradiographic technique on 67 piglets. Plasma ET was measured in 116 control, hypoxic, and recovery animals. In piglets exposed to hypoxia from birth, plasma ET was greater than normal for age (P < 0.05), and the binding density of ET-1 was increased in elastic arteries, muscular arteries, and veins due to an increase in the density of ET(A) binding (P < 0.05 for all vessel types). On recovery, plasma ET level became normal after 6 days. After 1 day of recovery, the binding density of ET-1 and ET(A) was normal in elastic arteries but was greater than normal in muscular arteries even after 6 days (P < 0.05). Exposure to hypoxia from 3 to 6 or from 14 to 17 days did not alter the plasma ET or the binding density in muscular arteries, but the density of binding of ET-1, ET(A), and ET(B) in elastic pulmonary arteries decreased (P < 0.05). On recovery, it returned to normal by 6 days. In summary, the increases in plasma ET and ET-1 and ET(A) binding density suggest a role for ET in the pathogenesis of hypoxic pulmonary hypertension in the newborn period. An initial normal period of adaptation is protective.

Aging↗